Biodegradable nanomaterials

CHAPTER FIVE

Biodegradable nanomaterials Katerina Anagnostou1, Minas Stylianakis1, Sotiris Michaleas2 and Athanasios Skouras1,2 1

Department of Electrical & Computer Engineering, Hellenic Mediterranean University Heraklion, Crete, Greece Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus

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5.1 Introduction Starting from 1970 the interdisciplinary approach between chemical, biological, and pharmaceutical sciences has led to the introduction of new applications in the medical field thanks to greater versatility in controlling the physical state, shape, size, and surface of polymers. This new knowledge has led to considerable innovation in the design and development of drug delivery systems (DDS): in those years began the study of reabsorbable controlled release systems of drugs, formed from biodegradable polymers (BPs). A thorough examination of the structure and properties of this type of materials led to the development of methods for their manufacture and the consequent production of materials—synthetic and not—, specific by type of application (Pillai and Panchagula, 2001). A polymer is a substance composed of repeating units, called monomers, held together by covalent bonds and its macrostructure may present itself as a linear, branched, or reticulated chain. It generally has a high-molecular weight, hence the name of macromolecule. Depending on the composition and arrangement of the monomers, they can be characterized as homopolymers or copolymers: the former consist in repeating the same unit for the entire length of the chain, the latter may have a sequence of two or more types of monomer in a more or less disordered manner. A polymeric material owes its physicochemical and mechanical properties to the composition, structure and molecular weight of the polymer chains of which it is composed. The polymers can be of natural origin (such as polysaccharides, nucleic acids, or proteins) or synthetic [such as polylactic acid (PLA) and polyurethane]. BPs exact discovery time cannot be easily traced, although one of their first medical application can be traced back to at least CE 100 (Nutton, 2013) as catgut suture made from sheep intestines. In regards with synthetic BPs, the first reports surface in the 1980s

Nanomaterials for Clinical Applications. DOI: https://doi.org/10.1016/B978-0-12-816705-2.00005-9

© 2020 Elsevier Inc. All rights reserved.

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Figure 5.1 List of biodegradable polymers showing their medicinal properties.

(Vroman, 2009). Applications of BPs have been utilized in many applications in clinical medicine, as depicted in Fig. 5.1, including tissue engineering and drug delivery. As the name implies, the main characteristic of BPs is their degradation by biological means. Degradation is defined as an irreversible process, which leads to a change of the structure of the material, in the form of loss of mechanical properties, damage, fragmentation, or depolymerization. Degradation is affected from the environment and can present a constant or variable speed over time. The human body uses mainly two processes to decompose large molecules dimensions: hydrolysis and enzymatic degradation. The synthetic polymers used in medicine are mainly decomposed by hydrolysis. The speed of this reaction and, consequently, the residence time of the polymer in the organism, are regulated by several factors: 1. Interaction of the polymer with water: the diffusion coefficient is important and, above all, water absorption in the polymer. The greater the hydrophilicity of the material, the greater the decomposition speed. 2. Crystallinity of the polymer: the amorphous regions of the material are less compact and allow for better penetration of water. The more crystalline a material is, the more it will resist degradation.

Biodegradable nanomaterials

3. Temperature has two effects that accelerates the reaction kinetics and makes more movable chains (if the glass transition temperature is exceeded). 4. Polymer structure: the presence of heteroatoms, hydrophilic groups and, in particular way, ethereal, ester, and urethane bonds facilitates degradation. Other factors such as water concentration, pH, and salt concentration can also influence the hydrolysis speed. The hydrolysis products of biocompatible polymers are often monomers that are disposed of thanks to normal metabolic body processes. For example, poly(lactic-co-glycolic acid) (PLGA) is decomposed into lactic acid and glycolic acid: the former is disposed of, similarly to that produced during intense physical activity in the muscles, through the kidneys or transformed into pyruvate, which enters the cycle of Krebs; the glycolic acid instead is used by the body for the synthesis of glycine and other amino acids. Practically a polymer is defined as “degradable” if it is broken down during the application or immediately thereafter; on the contrary, a material “not degradable” requires a much longer time for degradation than the duration of its application (Gopferich, 1996). BPs offer numerous advantages: • Chemically they are often inert in biological environments and exhibit less toxicity than nonbiodegradable materials. • They degrade in a controlled manner within the body thus allowing it to be easily absorbed or eliminated, avoiding the use of surgery for their removal and thus decreasing the discomfort for the patient. • They can be designed to allow adequate control over the kinetics of drug release. • They are naturally recycled by biological processes, as they are most often derived by plant processing of atmospheric carbon dioxide. BPs, as already stated, can be divided into two large categories: natural and synthetic polymers. The main polymers utilized so far in drug delivery applications are described below.

5.2 Natural polymers Biodegradable natural polymers or biopolymers derive from renewable resources, formed in nature during biological processes of different organisms. Chemical modification of these polymers is often required for improvement of their physicochemical and mechanical properties. Biopolymers can be further divided in polysaccharides, proteins, and bacterial polymers as depicted in Table 5.1.

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Table 5.1 Main biopolymers utilized as drug delivery systems (DDS) and their origin. Biopolymer Main polymers utilized Chemical structure Origin class

Polysaccharides

Proteins

Microbial origin

Starch

Seed, roots, tubers of potatoes, rice, etc.

Cellulose and derivatives

Cell wall of green plants

Chitosan

Crab shells

Hyaluronic acid

Extracellular matrix of tissues

Alginate

Brown algae, bacteria

Collagen

Connective tissue

Gelatin

Hydrolysis of collagen

Albumin

Serum protein

Polyhydroxyalcanoates

Bacterial

Poly-γ-glutamic acid

5.2.1 Polysaccharides Polysaccharides are polymeric carbohydrate molecules composed of monosaccharides bound together by glycosidic bonds. Their main function in living organisms is either structural or storage related. Polysaccharides include a large variety of biopolymers with different physicochemical properties, resulting mainly by the many different monosaccharides that compose them. Nevertheless, all of these biopolymers are biodegradable,

Biodegradable nanomaterials

biocompatible, widely available, and can be readily modified due to the presence of functional groups along their polymeric chain (Liu et al., 2008). Polysaccharides include cellulose, starch, alginic acid, hyaluronic acid, chitin, and chitosan.

5.2.1.1 Chitosan Chitosan is a linear polysaccharide consisting of repeating units of N-acetyl-D-glucosamine and D-glucosamine joined by (1-4)-β-glycosidic bonds. Generally, it is produced by alkaline deacetylation of chitin, widely distributed in nature as the main component of the exoskeleton of insects and crustaceans and of the cell wall of some fungi (Younes and Rinaudo, 2015). Unlike chitin, it is soluble in water under acidic conditions (pH less than 6) per effect of protonation of amine groups (pKa equal to 6.3), which gives the polymer a positive net charge. In addition to being biocompatible, nontoxic, and biodegradable, chitosan possesses a series of interesting biological properties that make it a good candidate for carrier of drugs. Thanks to its mucoadhesive properties, it prolongs the residence time of drugs at the site of absorption leading to a significant increase in their bioavailability (Ahmed and Aljaeid, 2016). Moreover, it exerts a strong antimicrobial action against both Gram-positive and Gram-negative bacteria. It also possesses immunoadjuvant, hemostatic, and cicatrizing properties, which justifies its use in tissue engineering and medicine applications regenerative.

5.2.1.2 Hyaluronic acid The very structure of hyaluronic acid, a polysaccharide composed of disaccharide units of D-glucuronic acid and N-acetyl-glucosamine connected by glycosidic bonds of type β (1,3) and β (1,4), in addition to its high biocompatibility, biodegradability, and nonimmunogenicity, gives it great potential as a DDS (Huang and Huang, 2018). This natural polymer is very soluble in water and thus the preparations obtained from it are highly unstable in physiological liquids and therefore not suitable for controlled drug release. This problem can be solved by derivatization with hydrophobic groups, which leads to the obtainment of temporarily insoluble polymers. An adequate choice of the substituent allows to obtain products without toxicity or immunogenicity and with good biocompatibility. The hyaluronic acid molecule carries a set of free hydroxyl and carboxylic groups, which can be used to directly bind the drug to the polysaccharide. In this way, during the physical process of the erosion and solubilization of the polymer matrix, a significant lowering of the drug release rate is obtained in the surrounding environment, due in large part to the time necessary for the chemical breakdown of these bonds (Khunmanee et al., 2017)

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5.2.1.3 Alginate Alginates are a family of linear polysaccharides consisting of two epimers: α-L guluronic acid (G) and β-D mannuronic acid (M). Its structure is formed from homopolymer sequences (MM or GG) between which sequences are found heteropolymeric (MG) (Lee and Mooney, 2012). The monomeric composition of alginate, the molecular weight, and the extension of the guluronic sequences emannuronics influence its properties (George and Abraham, 2006). The alginate is an important component present in brown algae as well as an exopolysaccharide of different bacteria. Since alginate is prepared in aqueous media offers an attractive alternative for the formulation of compounds that are unstable in organic solvents such as proteins. However, since cation-induced gel formation is reversible, a disadvantage of unmodified, alginate-based delivery systems is rapid drug release when exposed to monovalent ions in physiological media. 5.2.1.4 Starch Starch is a low-cost, abundantly available, environmentally friendly polysaccharide mainly extracted from potatoes, rice, and corn. It is a copolymer of amylopectin and amylose composed of D-glucopyranoside monomers linked with different glycosidic bonds. Starch, however, presents poor mechanical properties and a certain water sensibility. These problems can be addressed either by modifying the hydroxyl functionality as is the case with acetylated starch or by blending starch with other BPs. Starch acetate has a higher content of the linear amylose and is thus more hydrophobic and has better film-forming capability compared to native starch (Heinze and Koschella, 2005). Blending of starch holds the advantage that the material’s properties can be adjusted by modifying the composition of the blend while also being a low-cost process. 5.2.1.5 Cellulose and cellulose derivatives Cellulose is an omnipresent polysaccharide consisting of a linear chain of β(1-4) linked D-glucose units that forms the backbone of many excipients used in marketed drug products. It is the main component of the cell wall of green plants. The characteristic intramolecular hydrogen bonding results in cellulose being insoluble in most solvents, including water. This was addressed by the development of chemically modified celluloses (e.g., hydroxypropyl) that can be soluble both in water and organic solvents, thus opening the way for their use as DDS (Salimi et al., 2016; Moon et al., 2011).

5.2.2 Proteins Proteins are high-molecular weight polymers where amino acids act as monomers, linked together by characteristic amidic bonds. Being the main structural components in the human body, proteins have been extensively researched for various applications,

Biodegradable nanomaterials

including DDS. The most successful proteins so far in drug delivery include collagen, gelatin, and albumin. 5.2.2.1 Collagen Collagen is the main component of connective tissues and is synthesized by fibroblasts of connective tissue and bone osteoblasts. There are many types of collagen, united by three polypeptide chains that are assembled in a triple-helix supramolecular structure. Collagen in mammals can be rapidly degraded in its amino acid components by enzymes such as collagenase and metalloproteinases. On the other hand, it is a biomaterial difficult to sterilize without altering its original structure; therefore, the use of collagen for drug delivery could be problematic, also due to adverse immune reactions (Parenteau-Bareil et al., 2010). A valid alternative is represented by gelatin (Santoro et al., 2014). 5.2.2.2 Gelatin Gelatin is produced by acid-, alkali-, or enzymatic hydrolysis of collagen. To obtain gelatin, the triple-helix structure of the collagen is disintegrated, transforming the progenitor structure into a single-helix polymer (Kuijpers et al., 1999). Gelatin has the same properties of biocompatibility and biodegradability of collagen but is less prone to the induction of adverse immune responses. Gelatin is crosslinked with agents such as glutaraldehyde in order to achieve lower drug release rates (Santoro et al., 2014). 5.2.2.3 Albumin Albumin, a globular protein, is the most expressed serum protein with its main functions being, maintaining oncotic pressure and acting as a molecule carrier in the plasma (Hawkins et al., 2008). It has low immunogenicity and can be chemically modified easily. The natural transport function, the presence on its surface of aminic, carboxyl, and thiol moieties able to form covalent bonds with different drugs or other proteins, and cellular interactions provides rational for the exploitation of albumin for drug delivery (Larsen et al., 2016). Another interesting strategy is the fusion of albumin with drug/proteins by connecting the protein gene to that of albumin and subsequently expressing it in a suitable host. The main challenge for albumin remains the complete understanding of cellular interactions, which could lead to intracellular drug delivery applications.

5.2.3 Biopolymers of bacterial origin Bacterial polyesters and polyamides are another class of biopolymers presenting interesting properties, including biodegradability, biocompatibility, and almost no toxicity. They are produced by microorganisms while their composition can be modified by

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modifying the nutrients and/or the culture conditions. Polyhydroxyalkanoates and poly (γ-glutamic acid) are the main polymers studied as DDS. 5.2.3.1 Polyhydroxyalcanoates Polyhydroxyalcanoates (PHAs) are produced by bacteria as an energy reserve and source of intracellular carbon, under nutrient limitation conditions and in excess of carbon source. Several bacterial species can produce PHA, while the nature of the synthesized polymer depends on the starting monomers. The bacteria of the genus Ralstonia produce short-chain PHA (scl) using intermediates from fatty acids catabolism, while from the bacteria of the genus Pseudomonas originate medium-chain PHA (mcl) starting from intermediates of β-oxidation. The poly(3-hydroxybutyrate) (PHB) is the best known and studied both from the biosynthetic point of view and from that of the properties and uses (Kai and Loh, 2014). It was first identified in 1926 by Lemoigne, a microbiologist at the Pasteur Institute in Paris, as a constituent of the microorganism Bacillus megaterium in the form of lipid-like sudanophilic inclusions soluble in chloroform. Pure and perfectly isotactic and always presents the R configuration and is therefore optically active. The PHB extracted from bacteria has crystallinity, ranging from 55% to 88%. PHB has a highglass transition temperature and low-impact resistance, a problem addressed with the insertion of 3-hydroxyvalerate units in the PHB, which results in a poly (3-hydroxybutyrate-co-3-hydroxyvalerate) P copolymer with less fragility (Shrivastav et al., 2013). 5.2.3.2 Poly(γ-glutamic acid) This is a nonimmunogenic, biocompatible, anionic, BP made up of repeating units of L-glutamic acid, D-glutamic acid, or both, produced by microbial fermentation. The glutamic acids in poly(γ-glutamic acid) (γ-PGA) are polymerized via γ-amide linkages, so they are not susceptible to proteases. Its applications range from food industry to medical research including drug delivery and tissue engineering (Khalil et al., 2017). Optimization of the production and purification procedures in order to reduce costs is required for γ-PGA to become a more viable option in drug delivery.

5.3 Synthetic polymers Although for the first controlled release resorbable systems polymers of natural and semisynthetic origin were used, synthetic polymers have proven over time much more suited to this type of applications since being of nonnatural production, makes it possible to exercise greater control over their degradation profile and functionality. The main classes of synthetic BPs utilized thus far are summarized in Table 5.2.

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Table 5.2 Main synthetic biodegradable polymers utilized as drug delivery systems. Polymer class Main polymers General chemical Benefits utilized structure (where applicable)

Polyesters

Polyanhydrides

Poly lactic acid

Low cost Excellent mechanical properties

Polyglycolic acid

Monomer of natural origin Many commercial vendors

Poly(lactic-coglycolic acid)

Tunable degradation rate Highly processable

Poly-ε-caprolactone

High flexibility and processability

Poly(sebacic acid)

Monomer flexibility Tunable degradation rate

Poly-(orthoesters)

Controllable and pHsensitive degradation

Poly(alkyl cyanoacrylates)

Tunable degradation rate

Synthetic Pseudoaminoacids poly(amino acids)

Poly(ethylene glycol)-conjugated aminoacids

Variable structures depending on aminoacid

Enzyme-specific degradation Aminoacids as degradation products Increased circulation time

Polyphosphazenes

Synthetic flexibility Phosphorus polyvalency

Polyphosphates

Unique degradation kinetics Phosphorus polyvalency

5.3.1 Aliphatic polyesters Polyesters are the materials most studied in this field because of the presence of the ester bond in their skeleton, which can be hydrolyzed in the biological environment. The most used are polyglycolic acid, polylactic acid, and polylactic-co-glycolic acid surface, thus protecting the drug within the matrix (Singh and Tiwari, 2010). Aliphatic polyesters represent the class of synthetic BPs mainly researched. The synthesis of aliphatic polyesters with polycondensation of diols and dicarboxylic acids has

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been known since 1930. However, the low-melting point, high-hydrolytic instability, and low-molecular weights of the polymers initially obtained limit their use in mechanical applications. On the other hand, the susceptibility in hydrolysis of these polymers serves a variety of medical applications like absorbable sutures. These limitations placed research focus in new synthetic routes in order to form polymers of highmolecular weights. As a result, new routes like the ring-opening polymerization of cyclic diesters were developed. The monomers mainly used for biomedical applications are lactide, glycolide, and caprolactone. 5.3.1.1 Polyglycolic acid Polyglycolic acid was the first synthetic BP used as a resorbable and implantable DDS. Its use has given way to the design of devices that do not require an explant procedure, as opposed to the systems based on nondegradable materials previously used. Its first application dates back to 1962, as a bioabsorbable suture produced by the American Cyanamide Company (Singh and Tiwari, 2010). It is an aliphatic polyester obtainable at low cost and in a highly crystalline form (up at 45%
55% of crystallinity); it has a high-elastic modulus and a low solubility in solvents organic. It is characterized by a glass transition temperature is of 35 C
45 C and a very high-melting point (more than 200 C). It loses its strength in 1
2 months degrading through hydrolysis and undergoes a loss of mass within 6
12 months. Moreover, thanks to its high crystallinity, it has excellent mechanical properties: used in a copolymer, reinforces the structure of the material more than any other degradable polymer used for medical applications (Lakshmi, 2007). 5.3.1.2 Polylactic acid In the last 15 years, PLA has established itself among the most used BPs for the production of resorbable implants and devices. It belongs to the family of aliphatic polyesters and derives from lactic acid (monomer), of natural origin, produced by the bacterial fermentation of carbohydrates ( Jiang and Zhang, 2017). Unlike glycolic acid, lactic acid is a chiral molecule and occurs as enantiomer of type L or D. The polymerization of these monomers leads to the formation of semicrystalline polymers. The polymer deriving from the L-type enantiomer is the poly-L-Lactide (PLLA), having a degree of crystallinity of 37%, depending on the molecular weight and the production process. Presents a glass transition temperature of 55 C
65 C and a melting temperature of about 175 C. An important feature to consider is the very long degradation time, when compared with other polymers used as absorbable DDS: PLLA takes more than a year to degrade in the body through the hydrolysis process, and from 2 to 5 years to be totally expelled from the organism (Middleton and Tipton, 2000). This property derives from the high hydrophobicity of the polymer and is also influenced by the degree of the material’s porosity.

Biodegradable nanomaterials

The poly-DL-Lactide (PDLLA) (or more simply PLA) derives instead from the polymerization of a mixture of monomers of type L and D; it is totally amorphous, with a glass transition temperature of 45 C
60 C. Due to its noncrystalline nature, it has an elastic modulus lower than the PLLA, and for the same reason degrades faster: in 1
2 months it undergoes a loss of mechanical resistance and loses mass in 12
16 months (Maurus and Kaeding, 2004). Depending on the specific applications and needs, one can choose to use PLLA or PDLLA; generally, the polymer deriving from poly-D-Lactide (PDLA) does not find a great use as DDS. PLA can be easily obtained in the form of fibers, films, and sheets; it is degraded followed by hydrolysis of ester bonds and does not require enzymes that catalyze this reaction. Precisely for this reason, following manufacture, thermal stability is required to prevent spontaneous degradation and maintain the properties and molecular weight; in fact, for temperatures above 200 C, it degrades by hydrolysis, by cleavage of the main chain due to oxidation, and by intra- or intermolecular transesterification. The degradation of PLA depends from time, temperature, and the presence of lowmolecular weight impurities and catalysts (Cai et al., 1996). 5.3.1.3 Polylactic-co-glycolic acid It is a statistic copolymer obtained by copolymerization of cyclic dimers glycolic and lactic acid with the purpose of modulating the properties of the two homopolymers. Often identified by the ratio between monomers used, the PLGA, in its various forms, tends to be more amorphous than it is crystalline, with a Tg between 40 C and 60 C. Soluble in many common solvents, unlike the constituent homopolymers, the PLGA degrades to a speed directly proportional to the content of glycolic acid. Used for the first time in 1974 as a suture material, today finds various applications also thanks to the modularity of its properties: for example, in the form of nanospheres, nanofibers, microspheres, and microcapsules are used for controlled release devices of drugs, drugs chemotherapeutics, antibiotics, proteins, analgesics, antiinflammatories, and molecules of RNA. The problems related to the use of this polymer, however, are the difficulty of modulation of the degradation rate and the high acidity of the products resulting from the latter (Makadia and Siegel, 2011). 5.3.1.4 Poly-ε-caprolactone Poly-ε-caprolactone (PCL) is a semicrystallized aliphatic polyester obtained with a polymerization process by opening the caprolactone ring. It is used in some applications such as DDS for its biocompatibility and degradation properties in physiological environment. The PCL in fact, while undergoing a process of hydrolysis much slower compared to that of PLA, it is degraded in the body thanks to the action of enzymes. It has high flexibility and processability and can be obtained in the form of fibers or film. PCL is almost always used to form copolymers with PLA: high strength

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and low-glass transition point of the polycaprolactone give the final material greater ductility and robustness ( Jiang and Zhang, 2017). Traditional polyester-based DDS absorb water during degradation which leads to a bulk erosion of the system leading to stability problems, such as the hydrolysis of sensitive drugs. In addition, zero-order kinetic drug release was difficult to achieve. Therefore, investigators have begun research on highly hydrophobic polymers with low-hydrolytic stability, where degradation of the polymer may be limited to the surface, thus protecting the bulk material. The surface would degrade gradually thus giving even more control on the release kinetics, leading to the development of DDS composed of different BPs such as poly-(orthoesters) (POE), polyanhydrides, poly (alkylcyanoacrylates), and synthetic poly-aminoacids.

5.3.2 Poly-(orthoesters) Poly-(orthoesters) are hydrophobic polymers developed in the early 1970s and have evolved through four families, POE I
IV. Resulting hydrophobicity of the matrix limits water penetration, thus confining erosion to the surface and leading in a more controlled release of the drug, in contrast with bulk erosion of polylactides. POE IV is essentially a derivative of the most hydrophobic POE II containing a segment based on lactic or glycolic acid. As POE II is extremely hydrophobic, presence of water needed for the hydrolysis of the ortho esters is limited, leading to low-degradation rates. Addition of these segments provides a catalyst (ɑ-hydroxy acids produced by hydrolysis of the segments) for the hydrolysis of the ortho esters. Concentration of the ɑ-hydroxyl acids is directly related to the degradation rate, allowing for better control of the erosion process (Heller et al., 2002).

5.3.3 Polyanhydrides Polyanhydrides were first used in 1996 for controlled drug delivery devices after the Food and Drug Administration, characterized their degradability and biocompatibility properties through various in vivo and in vitro studies (Katti et al., 2002). The polyanhydrides derive from monomers containing the CO
O
CO functional group and were first reported in 1909 by Bucher and Slade. They are among the polymers that undergo the fastest hydrolytic degradation process, due to their aliphatic bonds in the basic structure extremely reactive in the presence of water. A property that has made them suitable for the production of DDS is to undergo surface erosion, thanks to their high degree of hydrophobicity combined with the tendency to a fast process of hydrolysis ( Jain et al., 2005). Synthesis is mainly achieved by condensation of diacids, open-chain anhydride polymerization, interfacial condensation, and dehydrochlorination of diacid chlorides.

Biodegradable nanomaterials

5.3.4 Poly(alkyl cyanoacrylates) Poly(alkyl cyanoacrylates) (PAC) present the unique property of undergoing ester side-chain hydrolysis by esterases. The biodegradation process is followed by solubilization and, precisely thanks to this characteristic, these polymers have been used for many years as a glue for tissues in surgery (Vauthier et al., 2003). The main advantage of PAC is that their degradation rate can be tuned by modifying the length of the alkyl chain. PAC rate of degradation is also correlated with toxicity (Kante et al., 1982). More specifically, smaller alkyl chains with higher rate of degradation exhibit some toxicity, whereas larger alkyl chains with lower rate do not. Little control on many factors regarding drug loading and release has led to different results and subsequently to no commercial DDS.

5.3.5 Synthetic poly(amino acids) Synthetic poly(amino acids) present many potentials advantages like biomaterials. Given the large number of existing amino acids, many different types of polymers and copolymers can be produced that easily bind drugs and small peptides. Many are highly insoluble and not processable, their degradation is difficult to control in vivo because they are enzymatically degraded, and the levels of enzymatic activity vary from person to person. Only a few of these can be used for drug delivery applications (e.g., polyglutamic acid derivatives). To tackle these problems pseudo-polyamino acids were proposed in 1984 (Kohn et al., 1986). The pseudo-polyamino acids, thanks to the presence of nonamide bonds between the amino acids, have better chemical
physical characteristics compared to polyamino acids. Other attempts include the preparation of copolymers containing blocks of aminoacids and synthetic polymers like poly(ethylene glycol) (PEG).

5.3.6 Inorganic biodegradable polymers So far, we have reported synthetic BPs of organic origin. However, there are also inorganic polymers that in their backbone instead of carbon have other atoms such as nitrogen or phosphorus. These polymers are considered remarkable biomaterials because of their exceptional features. 5.3.6.1 Polyphosphazenes Polyphosphazenes are hybrid polymers combining an inorganic backbone with organic side chains. More specifically the main chain consists of phosphorus and nitrogen atoms with alternating single and double bonds while organic substituents are linked to the phosphorus atoms as side groups. The phosphorous
nitrogen backbone exhibits extraordinary synthetic flexibility, while variation of side chains lead to polymers with different physicochemical characteristics and degradation rates

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(Teasdale and Brüggemann, 2013). In fact, depending on the side groups, polyphosphazenes can be biodegradable or nonbiodegradable. In contrast to organic BPs, presence of pentavalence phosphorus allows the development of prodrugs and or conjugation of targeting moieties. 5.3.6.2 Polyphosphates Polyphosphates is another class of phosphorus-containing polymers widely studied because of their structural similarities to biological macromolecules like DNA (Chaubal et al., 2003). Their backbone consists of repeating phosphoester groups, which possess unique degradation kinetics, and they can be modified with the introduction of functional groups to the pendant alkoxy or aryloxy groups (Singh et al., 2006). Phosphorus multivalency means their physicochemical properties can be easily tweaked. Under physiological conditions they are degraded due to hydrolysis or enzymatic cleavage of phosphate linkages.

5.4 Polymeric nanoparticles 5.4.1 Introduction Polymeric NPs are a novel addition to the field of pharmaceutical nanotechnology. They are a nanotechnology-based system fabricated for pharmaceutical purposes, otherwise known as nanopharmaceuticals. Nanopharmaceuticals may aid pharmaceutical nanotechnology in tissue engineering, disease prevention and treatment, and improvement of DDS (Bhatia, 2016). However, issues such as safety concerns, toxicity hazards, low biocompatibility, and physiological challenges result in limitations for the activity of nanopharmaceuticals. There is certainly a need for safe, biocompatible nanosystems with tunable properties and controllable activity. Polymeric nanoparticles (NPs) are currently being engineered and investigated as carriers for safe, efficient, and stable drug delivery to desired administration sites. Polymeric NPs show many novel properties which make them worthy competitors for other DDS. They are biodegradable, biocompatible, and nontoxic which makes them a safe option as carriers for DDS. An equally important feature is their tunable physical, chemical, and biological properties which provides controllable drug release motives, the ability to codeliver multiple drugs and specificity resulting in more efficient drug delivery and targeting of the administration site. Lastly, there are various fabrication methods for polymeric NPs with the possibility for production in large quantities.

Biodegradable nanomaterials

5.4.2 Properties—advantages of polymeric nanoparticles As stated earlier, biodegradable polymeric NPs present many properties that make them exquisite candidates for carriers in drug delivery. Their main advantages include the following: 1. Size: Polymeric NPs typically range from 10 to 1000 nm in size. The size of NPs gives them an advantage as a drug carrier because they are better suited for intravenous delivery compared to previously developed microsized DDS (Hans and Lowman, 2002). The smallest capillaries in the body have a diameter of 5
6 μm. Therefore, the size of particles circulating through the bloodstream must be significantly smaller than 5 μm, without forming aggregates, to avoid the formation of an embolism caused by the particles themselves. 2. Shape: Different NP structures can be engineered using various methods depending on the properties of the selected polymer (or polymers) and the drug that is to be loaded and delivered. In this context, two major categories of polymeric NP drug carriers can be named based on their form: nanospheres (100
200 nm) and nanocapsules (100
300 nm) (Kumari et al., 2010; Letchford and Burt, 2007). The two forms differ in the way that the polymer is organized structurally. In the case of a nanosphere, the polymer forms a colloidal particle, whereas in the case of a nanocapsule the polymer forms an outer shell wherein exists an aqueous or oily environment (Calzoni et al., 2019). In both cases, depending on the structural organization of the polymeric NP, the drug can either be adsorbed to the surface of the NP or become entrapped within the NP itself (encapsulation). An addition to the concept of a nanosphere is that of a polymersome (5 nm
5 μm). These particles are inspired by the structure of liposomes and consist of a bilayer of amphiphilic block copolymers which surrounds an aqueous environment. The amphiphilic polymers mimic the lipid bilayer of liposomes which inspired the fabrication of this particular polymeric NP and the aqueous center provides an environment in which hydrophilic drugs can be loaded (Letchford and Burt, 2007). Amphiphilic polymers also form polymeric micelles through spontaneous selfassembly due to hydrophobic interactions. Self-assembly formulations involve intermolecular and intramolecular interaction between the polymer molecules and the drug itself. In the case of micelles, amphiphilic polymers accumulate in such a way creating a two-phase system. The polymers orient themselves in such a way that the hydrophobic component phases inward, away from the hydrophilic environment, whereas the hydrophilic end of the polymer molecules is attracted to the environment and remains on the outer part of the micelle structure (Letchford and Burt, 2007; Karlsson et al., 2018). 3. Biocompatibility and biodegradability: Natural polymers, especially, namely, polysaccharides and protein-based polymers, show excellent biocompatibility as they

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4.

5.

6.

7.

8.

can be broken down into polysaccharides and peptides respectively by enzymatic degradation. These biomolecules can then be easily metabolized by the body without any harmful side effects (Nair and Laurencin, 2007). The biodegradability of polymeric NPs not only contributes to their biocompatibility, put it is also a major factor in their drug release ability. Safe, less toxic, nonimmunogenic: The use of polymeric NP’s as carriers in anticancer drug delivery has shown decreased toxicity, as the polymeric component of the carrier provides protection for the drug and limits its interaction with healthy cells (Brewer et al., 2011). Engineered specificity: Depending on the method of preparation polymeric NP are a suited choice for intracellular and site-specific drug delivery (Bhatia, 2016). These systems have the ability to deliver higher concentrations of the drug to specific administration sites, since they can be specially modified in terms of size and surface characteristics in order to reach a specified target cell. Tunable physical, chemical, and biological properties: The use of polymeric NPs as drug carriers provides the liberty of controlled and long-term release rates, prolonged circulation times, and prolonged bioactivity. All these features are crucial in the efficient activity of the drug carrier. The ability to modify drug release motives from the polymeric NPs have made these systems promising contenders for cancer therapy, vaccine delivery, delivery of antibiotics, and contraceptives. Adding PEG to the polymer of the NP has been shown to increase the circulation time of the nanocarrier by hindering uptake by the reticuloendothelial system (RES). PEG achieves this by inhibiting the binding of proteins on the carrier’s surface therefore intercepting its recognition by the RES (Gref et al., 2000). Stability: Polymeric NPs can stabilize volatile pharmaceuticals, protecting them from the environment until the reach the administration site. There exist a variety of polymers from which suitable ones may be chosen for loading of either hydrophobic or hydrophilic drugs. Multiple drug codelivery: Ability to codeliver multiple drugs with synergistic effects (Brewer et al., 2011). The codelivery of multiple drugs in the same polymeric NP carrier overcomes issues such as multidrug resistance of tumor cells and achieves synergistic effects between different drugs (Bhatia, 2016). Wang et al. developed a polymeric NP carrier consisting of hyaluronic acid-decorated PLGA, pluronic F127 and chitosan for the codelivery of doxorubicin hydrochloride and irinotecan, which are a hydrophilic and hydrophobic anticancer drug, respectively. This dual-DDS shows high efficacy and increased effect against cancer stem cells in vitro and in vivo, which the researchers attributed to the synergistic activities of the two anticancer drugs as well as the capability of the polymeric NPs in efficiently delivering higher amounts of the drugs to the target cells (Wang et al., 2015).

Biodegradable nanomaterials

Figure 5.2 Surface adsorption and encapsulation of drug in nanospheres and nanocapsules. Courtesy from Kumari, A., Kumar Yadav, S., Yadav, S.C., 2009. Biodegradable polymeric nanoparticlesbased drug delivery systems. Coll. Surfaces B Biointerf., doi:10.1016/j.colsurfb.2009.09.001.

9. Multiple fabrication methods: The most suitable fabrication method for synthesizing polymer NPs depends on the properties of the polymer and the nature of the drug that is to be loaded for delivery. The two general categories of fabrication processes are top down and bottom up (Figs. 5.2 and 5.3).

5.4.3 Polymeric nanoparticles preparation Nanoparticulate systems can be prepared by utilizing different methods depending on the characteristics of the polymer and active ingredient, the site of action, and the therapeutic regime. The most commonly used techniques for the formulation of NPs for drug delivery involve the use of preformed polymers. 5.4.3.1 Emulsion—solvent evaporation This method, widespread due to its simplicity and versatility, was originally adopted for the encapsulation of lipophilic drugs. The polymeric material and the active ingredient are dissolved in a volatile organic solvent, immiscible with water (dichloromethane, chloroform, or acetonitrile), and the solution obtained is emulsified with an aqueous phase containing suitable stabilizing agents. The solvent is then evaporated, generally at elevated temperatures and reduced pressure, with consequent precipitation

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Figure 5.3 Schematic summary of different methods for nanoparticles synthesis.

of the polymer and formation of solid NPs. In the case of hydrophilic drugs, instead, a multiple water/oil/water emulsion (w/o/w) is required. The aqueous solution of the drug is emulsified with an organic phase consisting of solvent and polymer, so as to obtain a primary emulsion w/o (water/oil). The mixing of this first emulsion with an excess of water, under continuous stirring, generates the second emulsion w/o/w, from which the solvent can be removed by evaporation or extraction (Chiellini et al., 2008). The main drawback of this method lies in the use of organic solvents, which, in addition to being significantly toxic, can compromise the stability of the drug incorporated within the NPs (Park et al., 2005). 5.4.3.2 Coacervation Coacervation is a physical phenomenon of phase separation, typical of polymer dispersions, which occurs due to changes in pH and temperature or due to the addition of salts or solvents. This process is widely exploited for the preparation of micro- and nanocapsules, constituting one of the most common approaches also at the industrial level. After dispersing the active principle in a solution of the chosen polymer, coacervation of the system is induced leading to deposition of the polymeric material on the surface of the drug particles to form a continuous layer. The solidification of the

Biodegradable nanomaterials

coacervate, obtained by cooling or desolvation, leads to the formation of a rigid and resistant membrane containing the drug (Vilar et al., 2012).

5.4.3.3 Nanoprecipitation, coprecipitation, and dialysis In the previous techniques, the formation of NPs occurs as a consequence of the removal of the solvent from the polymer solution in the presence of a nonsolvent. In the nanoprecipitation method, the polymer solution containing the drug and any stabilizing agents is added dropwise to a nonsolvent, miscible with the solvent used to dissolve the polymer. NPs are formed instantly thanks to the rapid desolvation and aggregation of the polymer chains. The encapsulation efficiency is poor in the case of hydrophilic drugs, which tend to spread rapidly in water as soon as the organic phase in which they are dissolved (acetone and ethanol) comes into contact with an aqueous solvent (Legrand et al., 2007). A variant, certainly more advantageous for the encapsulation of water-soluble molecules, is represented by coprecipitation. The polymeric material is dissolved in a water miscible solvent and injected into an aqueous solution of the active ingredient. This procedure does not require the use of aggressive solvents and therefore allows the incorporation of proteins and peptides into the NPs without altering their functionality. In addition, with the aforementioned methods, dialysis also allows obtaining particles with a very narrow size distribution. A solution of the polymer, the active ingredient, and a surfactant in an organic solvent is prepared and placed inside a dialysis tube with adequate cutoff and dialyzed against a nonsolvent miscible with the previous one. The solvent inside the semipermeable membrane is displaced, which determines the loss of solubility and the progressive precipitation of the polymer in the form of NPs. The formation of large aggregates and their interaction with the dialysis membrane considerably limit the applicability of this process (Piras et al., 2010). 5.4.3.4 Ionic gelation NPs can form following the interaction of polyelectrolytes of opposite charge, generally operated in aqueous media. Polymers most used in this type of formulation are of natural and semisynthetic origin, such as alginate, chitosan, hyaluronic acid, pectin, and carboxymethylcellulose. The mixing of a polymeric solution containing the drug with an aqueous solution of polyvalent ions of opposite charge determines the three-dimensional crosslinking of the polymeric chains with consequent formation of stable complexes. Thanks to its mild preparation conditions, ionic gelation is particularly suitable for labile active ingredients such as proteins and nucleic acids (Chiellini et al., 2008).

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5.4.3.5 Spray drying Spray drying is a relatively new method, which offers several advantages, such as speed, good reproducibility, and scalability of the process, without a particularly high cost. A solution (or a dispersion) of the active ingredient in a suitable polymer solution is prepared. The atomization of this solution (or suspension) inside a hot air stream generates nanometric drops, from which the solvent evaporates rapidly with consequent formation of solid particles (He et al., 1999).

5.4.4 Drug release mechanisms The release of the drug from NPs occurs through a combination of diffusion and degradation mechanisms. Regarding the nanocapsules, release is controlled mainly by the diffusion of the drug through the polymeric membrane that surrounds it or the aqueous microporous network that interpenetrates the dense areas of the membrane. The active principle is released under the influence of a concentration gradient, according to a diffusion mechanism regulated by Fick’s first law: dM dC 5 2 DS dt dx

(5.1)

where dM/dt represents the diffusion rate, dC/dx is the concentration gradient through the membrane, D is the diffusion coefficient, and S is the overall surface area of the system. At equilibrium, drug release is constant over time and largely depends on the diffusion capacity of the drug, therefore on its affinity for the membrane, on the nature, on the thickness, and on the porosity of the membrane (Chien and Lin, 2007). In the case of nanospheres, the active ingredient is released through diffusion processes as well; however, the release rate and the concentration gradient at each point of the polymeric matrix vary as a function of time due to the continuous decrease in the quantity of drug contained within the system. In this case, the diffusion phenomenon is more correctly described by Fick’s second law: @ϕ Dð@^2ϕÞ 5 @t ð@x^2Þ

(5.2)

where ϕ is the concentration, ϕ 5 ϕ(x, t) is a function that depends on location x and time t, t is time, D is the diffusion coefficient, and x is the position (length). Furthermore due to interaction with biological fluids, the polymeric material can undergo hydrolytic and/or enzymatic degradation. This process contributes significantly to the release of the drug, also influencing rate of diffusion through the matrix or the polymeric membrane. The chemical composition of the polymer results therefore, decisive in the drug release kinetics making optimization of its activity profile possible (Vilar et al., 2012).

Biodegradable nanomaterials

Finally phenomena of solvation and swelling of the NPs may occur: the hydration of these systems within biological fluids causes distension and relaxation of polymeric chains, allowing the encapsulated agent to diffuse in the external environment (Peppas et al., 2000). This process is especially important in the case of hydrogels, that in the presence of water are able to increase up to five times their own volume. Theirs swelling can be induced by specific stimuli, such as changes in pH, temperature, or ionic strength, guaranteeing even more precise release control.

5.4.5 Targeting A crucial area of focus in drug delivery is the accurate targeting of a desired cell or tissue. In DDS, targeting refers to the drug carrier’s ability to deliver the cargo to the correct site at the correct time. An ideal and efficient nanocarrier should recognize a specific target cell or tissue, bind to it and deliver the drug all while avoiding unwanted drug induced side effects to healthy cells and tissues. Polymeric NPs may have engineered specificity through surface functionalization and manipulation of their tunable properties, allowing them to deliver a higher concentration of a drug to a desired site. DDS follow two major targeting mechanisms: Passive targeting and active targeting. In passive targeting, the NP reaches the target administration site passively, without the need for attaching additional ligands to serve this purpose. Active targeting, on the other hand, is a term that describes specific interactions between the drug carrier and the target cells, usually through specific ligand
receptor interactions. In active targeting, a ligand is used as a homing device through which the nanocarrier is conjugated to the target cell or tissue wherein the pharmaceutical agent is released after endocytosis (Varshosaz and Farzan, 2015). 5.4.5.1 Passive targeting The NP carrier reaches the target administration site without the aid of conjugated target-specific ligands to serve as homing devices. An example of passive targeting is the preferential accumulation of chemotherapeutic agents in solid tumors. This occurs as a result of the enhanced vascular permeability of tumor tissues compared with healthy tissue (Kaparissides et al., 2006). The NPs accumulate preferentially in the neoplastic tissues of the tumor as a result of the enhanced permeability and retention (EPR) phenomenon, first described by Maeda and Matsumura (Maeda, 2012; Matsumura and Maeda, 1986). The EPR is the result of the abnormal vasculature and impaired lymphatic drainage within neoplastic tissues. The size of NP drug carriers allows them to enter the tumor tissues through the EPR phenomenon (Bazak et al., 2014). Passive targeting holds disadvantages compared to active targeting. The NPs encounter obstacles on the route to the target site, namely, extracellular drug release and uptake by to nontarget cells.

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5.4.5.2 Active targeting In this targeting mechanism, the surface of the NP carrier is functionalized with ligands designed to act as homing devices by recognizing and binding to specific administration sites. These homing devices can be small organic molecules, peptides, antibodies, designed proteins, and nucleic acid aptamers. For example, specific antibodies can be used as homing devices for targeting of tumors. These antibodies recognize characteristic molecules on the tumor’s surface, which do not exist on healthy cells. By conjugating these antibodies to the NP, the DDS can then be led specifically to the tumor cells while leaving the normal cells unaffected (Abdolahpour et al., 2018). Since ligand
receptor interactions can be highly selective, this could allow a more effective targeting of the desired site, making active targeting a more appealing route than passive targeting. The advanced specificity due to active targeting also lowers toxicity and unwanted side effects that occur with nonspecific drug delivery to untargeted cells and tissues (Fig. 5.4).

Figure 5.4 Active targeting of tumor cells. The ligands on the nanoparticle surface recognize and bind to receptors on the tumor cells resulting in endocytosis Adopted by Zhang L., Li, Y., Yu, J. C., Chemical modification of inorganic nanostructures for targeted and controlled drug delivery in cancer treatment, 2014, J. Mater. Chem. B, 2, 452.

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5.4.5.3 Tumor targeting Utilizing polymeric NPs for tumor targeting is based on both passive targeting via the EPR effect and active targeting through surface ligands (Bhatia, 2016). According to Bae and Park (2011), the active targeting of tumors is assisted first by the EPR effect through which the drug-carrying NPs leave the blood stream and reach the general target area. There ligand
receptor interactions occur between the NP drug carrier and the targeted tumor cells. According to their perspective, the EPR effect and blood circulation time of the drug carrier are increased by the PEGylation of the NPs, that is, modification of the NPs with PEG. The improved EPR and circulation in the blood stream assists the drug carrier to reach the general target area more efficiently so that the active targeting may occur. Through using NPs as drug carriers, the drug’s distribution is limited to the target organ, and exposure to healthy tissues and organs is limited. Verdun et al. (1990) studied the effects of doxorubicin entrapped in polyisohexylcyanoacrylate-based NPs in mice compared to free doxorubicin. They found higher concentrations of the drug in the liver, spleen, and lungs of the mice treated with the encapsulated doxorubicin compared to the mice treated with the free doxorubicin. This shows the targeting ability of the nanocarrier and its recognition and preference of these specific organs. Distribution study cyclic arginylglycylaspartic acid (RGD)-doxorubicin-NP comprised of inulin multimethacrylate with a targeting peptide was carried out by Bibbly et al. in tumorbearing mice. Results showed that the drug concentration in the liver increased over time and decreased in the heart, lungs, kidneys, spleen, and plasma. This accumulation in the liver resulted in the maximum injected dose resulting in the liver and only a minute percentage reaching the tumor 48 hours after administration (Bibby et al., 2005). This study, as well as others, reveals the tendency of NPs to accumulate in the liver via uptake by the mononuclear phagocytic system (MPS). Therefore a challenge for tumor targeting with nanocarriers is to avoid their uptake by the MPS. However, this phenomenon can be manipulated to efficiently deliver chemotherapeutic agents via NPs to tumors in MPS-rich organs and tissues, for example, hepatocarcinoma, gynecological cancers, mall cell tumors, and others. Due to this effect, conventional anticancer drugloaded NPs are limited to MPS-rich organs (Bhatia, 2016; Fig. 5.5).

5.5 Clinical applications of biodegradable nanoparticles 5.5.1 Introduction The use of BPs is particularly appealing in clinical practice as these materials, due to their biodegradable nature, get eliminated from the body after fulfilling their purpose.

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Figure 5.5 Tumor sites can be reached either by passive targeting (EPR effect) or/and active targeting (Ligand - Receptor interaction).

Due to their vast versatility in nature and structure BPs can be tailored to possess specific, physical, chemical biological, functional, biomechanical, and degradation properties, which can serve the purpose of particular biomedical applications. The medical applications of BPs cover a rather heterogeneous field ranging from tissue engineering and tissue adhesives to implants and DDS. Several biodegradable polymeric materials have extensively been used with minor modifications for decades as sutures, orthopedic pins and nails, hemostatic sponges, fixation plates, and filaments. These materials bear a known safety profile, and their use in humans is approved by health authorities. Repurposing of these materials is a very cost-effective strategy, taking into account the time and effort needed to introduce a new material in clinical use. The plasticity of their polymeric nature allows modifications and varying compositions to be used to fit the purpose of new biomedical applications. Most of the already known natural and synthetic biodegradable polymeric materials can be formulated in the nanoscale matching the scale of biological systems, such as viruses, membranes, and protein complexes which are natural nanostructures. In this context, NPs with variable structure and properties have been formulated for various therapeutic applications (Song et al., 2018). The use of BPs as nanocarriers in drug delivery is particularly promising in drug development. Several studies have showed that BPs can be used to enhance biocompatibility, provide better encapsulation, and sustained release of drug molecules (Kumari et al., 2016). The potential of providing site-specific delivery for drugs, biomolecules, proteins, and peptides has led to a huge research output in this field.

Biodegradable nanomaterials

5.5.2 Regulatory aspects Despite the huge research efforts and investment by academia and pharmaceutical companies, regulatory approvals of novel nanomedicine products have not exceeded 10%, mostly because of failures in terms of efficacy and safety profiles during nonclinical and clinical studies. Regulatory guidance on nanomedicines is yet evolving and appears to be rather stratified and far from unambiguous across, the globe. A case by case approach is generally applied and request for product specific scientific advice by applicants is highly encouraged by regulatory agencies. Whatsoever there have been developed several concept papers by the European Medicines Agency (EMA) and a concise guidance document by the Food and Drug Administration (FDA) (Musazzi et al., 2017). Even if a BP is well characterized and extensively used in clinical practice in the macro- or microscale, its nanoscale applications undergo a separate and extensive regulatory review, due to the different toxicological profile of particles with dimensions less than 1 μm. Even minor changes in composition and/or physicochemical properties of NPs could result in clinically significant changes regarding pharmacodynamic, pharmacokinetics, and toxicity. Therefore, detailed characterization of drug products, identification of the critical attributes of the products, and the manufacturing process to achieve batch to batch consistency are a prerequisite along with in depth studies of how quality aspects of the product influence safety and efficacy profiles of the product. Safety concerns regarding NPs include potential infusion reactions, hypersensitivity reactions, oxidative stress, biodistribution and permanence, impact on immune system (Halamoda-Kenzaoui and Bremer-Hoffmann, 2018), unexpected toxicity effects due to increased reactivity, and permeability (Sufian et al., 2017).

5.5.3 Properties of biodegradable nanoparticles (BNPs) which impact clinical use The mechanical properties of BPs can easily be manipulated to fit the purpose of use. Strong mechanical properties are generally required for materials to be used as tissue adhesives or for tissue engineering, that is, the material should remain sufficiently strong until the surrounding tissue has healed, while for drug delivery more processable forms are required. Degradation time must match the time required for biomedical application. In vivo metabolism of the polymer matrix after fulfilling its purpose should invoke nontoxic constituents that can be easily eliminated to avoid a toxic response. Furthermore, material should be easily processable in the final product form with an acceptable shelf life and easily sterilized. The size and shape of NPs may affect solution dynamics in blood vessels. For example, it has been shown that NPs larger than 200 nm are collected in liver and

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spleen. Spherical geometry is typical for NPs designed for intravenous delivery to facilitate rheology and reduce immunogenicity (Ahlawat et al., 2018). Long rodshaped NPs on the other hand have been proved to show longer blood circulation and a highest bioavailability compared with short rod and spherical NPs (Zhao et al., 2017). Surface composition can also affect the course of elimination after delivery. Surface hydrophobicity enhances plasma protein adsorption and removal through opsonization and MPS. Surface charge can also affect the in vivo fate of NPs. Positively charged NPs are more quickly eliminated than negatively charged ones, while neutral NPs persist longer in blood. Surface characteristics can also affect sticking to vascular walls and uptake as well as cell removal by efflux pumps. NPs entering blood circulation tend to be favorably collected at sites of inflammation, that is, injuries, tumors, and infections. This constitutes a passive targeting due to the loose vasculature of endothelial cells, an effect known as EPR. This effect can be significantly enhanced by prolonging the presence of NPs in blood circulation by making NP invisible to plasma proteins. Stealth properties can be added by coating of NPs with hydrophilic or neutral groups after absorption or making copolymers of BPs with hydrophilic polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), PEG, or polysaccharides. The presence of hydrophilic and neutral chains at the surface can repel plasma proteins which results in prolonged presence in blood circulation and enhanced bioavailability (Suk et al., 2016). Modification of the NPs surface can also include conjugation with moieties that promote active targeting of tumor cells through NPs to overexpressed receptors of tumor cell membrane and phagocytosis or endocytosis mechanisms (Pillai, 2014).

5.5.4 Approved and investigational drugs with biodegradable polymeric nanoparticles of natural or synthetic origin In a recent analysis (D’Mello et al., 2017) of almost 350 submissions in FDA of nanomaterial-containing drug products since 1973, liposomes were the most prevalent category (33% drug products), followed by nanocrystal-containing drug products (23%). Emulsions formed 14% of the submissions, iron
polymer complexes 9% and micelles 6%. Drug products containing other nanomaterials, such as drug
protein complexes, drug
polymer complexes, and polymeric NPs, accounted for 14% of the overall applications. In another review (Bobo et al., 2016), a list of FDA-approved nanomedicines included among others, 2 drugs with protein NPs combined with drugs or biologics and 15 drugs containing polymer NPs with drugs or biologics. Most of these drugs were proteins PEGylated to improve stability, circulation time, or immunogenicity profile. Regarding material categories under investigation, it was shown that micellar, metallic, and protein-based particles entering the development process are increased in comparison to what has previously been approved.

Biodegradable nanomaterials

Natural and synthetic polymers have been explored for the synthesis of biodegradable NPs for drug delivery of anticancer, psychotic, antimicrobial and plant isolated, protein, peptides, and drugs. Natural polymers include albumin, gelatin, and chitosan, whereas synthetic polymers such as PLGA, PLA, PCL, and PACare drawing increasing attention for the last two decades (Kumari et al., 2016). The most common applications include development of improved chemotherapeutic delivery systems and improving oral bioavailability of hydrophobic and peptide/protein drugs. Future trends include application of biodegradable NPs in DNA/RNA delivery and gene therapy. 5.5.4.1 Anticancer drugs Tumor targeting with single or multiple chemotherapeutic agents to reduce drug doses and produce synergistic effects is a very appealing strategy in cancer research. Various polymers with a wide range of physicochemical properties have been utilized for delivery of cytotoxic drugs or other therapeutic agents (e.g., chemosensitizers, differentiation-inducing, and neovasculature disruption agents). Biodegradable materials used for this type of NPs include natural polymers (e.g., proteins, gelatin, chitosan) as well as synthetic polymers such as PLGA, poly(ethylenimine), poly(L-lysine), and PEG (Mokhtarzadeh et al., 2016; Afsharzadeh et al., 2018). Several approved and investigational drugs will be presented below. Protein NPs can encompass drugs attached to endogenous protein carriers, modified proteins where the active therapeutic is the protein itself, or composite functionalized platforms that rely on protein motifs for targeting delivery of the therapeutic agent (Bobo et al., 2016). Early protein NPs exploited the natural properties of serum proteins to facilitate dissolution and transport of drug moieties in blood circulation. An early example of a protein-based nanodrug is Abraxane, which contains albumin NPs (130 nm) conjugated with paclitaxel and was approved in 2005 by FDA. It was designed to improve paclitaxel chemoterapeutic applications by eliminating the need for use of the toxic solvent Kolliphor to solubilize paclitaxel (Bobo et al., 2016). Albuminbound paclitaxel NPs improved infusion time and eliminated the need to concomitantly administer antihistamines and dexamethasone to prevent an immune reaction to Kolliphor. Pazenir is the first generic of Abraxane in EU, another NP albumin-bound paclitaxel, which has been authorized in the EU since 2008. Studies have demonstrated the satisfactory quality of Pazenir. A bioequivalence study versus the reference product Abraxane was not required as Pazenir is administered intravenously and the NPs dissociate rapidly and because of the qualitative and quantitative compositions and the nature and behavior of the products (EMA/CHMP/147314/2019, 2019). After the success of Abraxane, several additional albumin-bound NPs (NABs) have entered clinical trials for the purpose of improving the efficacy and safety of other drugs (Patra et al., 2018). Among these are NAB-docetaxel, NAB-heat shock protein inhibitor, and NAB-rapamycin (Gonzalez-Angulo et al., 2013).

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Ontak (denileukin diftitox, Eisai, Inc.) is an example of protein NP drug combining active targeting proteins and cytotoxic molecules, which was approved in 2008 (Ventola, 2017). A major difference from Abraxane is that instead of using an unmodified protein it utilizes engineered particle complexes designed to enable active targeting (Havel, 2016). It is an interleukin (IL)-2 receptor antagonist that was initially designed to treat an aggressive form of non-Hodgkin’s peripheral T-cell lymphomas by targeting the cytocidal action of diphtheria toxin toward cells that overexpress the IL-2 receptor on T cells (Foss, 2006). Chitosan polymers: Chitosan-based NPs have been developed for the delivery of several combination chemotherapeutic schemes as well as gene carriers. Cationic polymeric NPs of camptothecin and curcumin have been prepared for synergistic colon cancer combination chemotherapy (Xiao, 2015). In another report, PEGylated chitosan NPs were loaded with both methotrexate as a targeting agent against folate receptors and mitomycin C, resulting in increased synergistic anticancer effect (Jia et al., 2014). Chitosan-based NPs have also been prepared for combinations of gefitinib agents with shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells (Yu et al., 2015) Gelatin has also been used as a NP carrier system for paclitaxel forming an amorphous water-soluble system allowing rapid drug releases at the target site (Lu et al., 2004). PLGA is listed as a safe material for human use by FDA, and research shows that PLGA NPs have great potential for the delivery of bioactive agents and applications in gene and vaccine delivery. It is commonly used blended with other polymers such as polypropylene fumarate, polyvinyl alcohol, or chitosan to moderate its acidic nature. Cisplatin (Avgoustakis et al., 2002), Docetaxel (Esmaeili et al., 2008), and Paclitaxel (Wang et al., 2011) are major chemotherapeutics that have been encapsulated in various PLGA nanosystems. Recently PLGA NPs surface engineered with hyaluronic acid for targeted delivery of paclitaxel to triple negative breast cancer cells were developed and showed improved cellular uptake (Cerqueira et al., 2017). Other applications are the encapsulation of Curcumin (Ranjan et al., 2012) and 9-NitroCamptothecin (Ahmadi et al., 2015). PCL is another promising polymer with great biodegradable properties at physiological pH. Various PCL-based NP systems have been investigated for enhances and better targeted delivery of Docetaxel (Zheng et al., 2009), Vinblastine (Prabu et al., 2008), Tamoxifen (Shenoy and Amiji, 2005), and Taxol (Ma, 2005). 5.5.4.2 Nanoparticles for oral delivery Improvement of oral bioavailability of drugs through NP formation is a widely investigated strategy. NPs formation can improve solubility of hydrophobic drugs and protect

Biodegradable nanomaterials

labile peptide and protein drugs and vaccines against the enzymatic and hydrolytic degradation in the gastrointestinal track. Uptake of NPs following oral administration has been shown to occur through apical sodium-dependent bile acid transportermediated cellular uptake, chylomicron transport pathways, and lymphatic uptake of the NPs by the Peyer’s patches in the gut-associated lymphoid tissue (Kim et al., 2018). Bioavailability of antifungal agents has been improved utilizing NPs delivery methods (Pandey et al., 2005) For example, itraconazole encapsulated in PLGA NPs showed enhanced intestinal permeability in an ex vivo study (Alhowyan et al., 2019). Another interesting goal remains the formulation of peptide and protein drugs such as insulin for oral delivery (Wong et al., 2017). In a recent paper, d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-emulsified PEG-capped PLGA NPs as a potential drug carrier for the oral delivery of insulin were synthesized and tested in diabetic rats by oral administration providing encouraging results (Alhowyan et al., 2019). 5.5.4.3 Future trends: nanoparticles for vaccines and gene therapy Polynucleotide and DNA vaccines present certain advantages over many conventional protein-based vaccines presenting better immunization efficiency (Hasson et al., 2015), lower production cost, and better stability profile and handling properties (Xu et al., 2014). BNPs can be effective carriers for DNA vaccines. A nano-chitosan-based DNA vaccine encoding T-cell epitopes of Esat-6 and FL was found to be effective against Mycobacterium tuberculosis infection in mice (Feng et al., 2013). In the field of gene therapy development of biodegradable nanomaterials for oligonucleotide delivery present an excellent opportunity to resolve safety problems usually encountered with either viral or other nonviral vectors. Improving gene transfer activity and functional quality of nanocarriers to optimize and target gene delivery are currently the biggest challenges in developing and applying effective strategies in the use of BPs as carriers for gene therapy (Mokhtarzadeh et al., 2016).

5.6 Future perspectives The use of polymeric NPs as nonviral DDS seems to be a critical area in future nanopharmaceutical research. It is evident that polymeric NPs may offer many advancements in drug delivery and will continue to attract attention from researchers of this field. There has been extensive research regarding nanosized drug carriers based on natural and synthetic polymers; however, there is need for this research to be extended

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into in vivo studying and clinical trials. The application of polymeric NPs as drug carriers has been expanded to serve the delivery of antibiotics, anticancers drugs, vaccines, and genes. This wide range of application is owed not only to the polymers’ intrinsic properties, that is, biocompatibility, biodegradability, nontoxicity, but also to the ability of polymeric NPs to be modified and functionalized to meet certain requirements. These particles can be engineered to have specific properties to aid them in efficient drug targeting and drug release, such as increase circulation time, active targeting of administration site through receptor recognition, and decreased recognition by the immune system. Looking at polymeric NPs from a chemical perspective, it is evident that there is much room for the generation of new and improved polymers. Chemical modification of polymers may lead to the engineering and fabrication of a new range of polymers with optimal chemical, physical, and biological properties. Through modification of polymeric NP drug carriers can be made to achieve improved targeting ability, stimuli-triggered drug release and targeted codelivery of multiple drugs. Much research has been carried out in the case of tumor targeting and anticancer drug delivery via polymeric nanocarriers. Among the future advancements in polymeric NP drug delivery technology, expanding their field of effect to allow treatment of even more pathologies, that is, immune system, and genetic diseases is very high on the list. There is a need for the development of large-scale fabrication processes for preparing large amounts of polymeric NPs. These fabrication methods should be economic, time efficient, and allow for the control of the particle size, the surface properties, and the drug release motives. Despite the advancements made in research of polymeric NP drug carriers, very few examples are currently in clinical trials. There is a need for in vivo testing to better overcome obstacles encountered during in vitro research and enrich the results and information collected thus far. It should be noted that even though these DDS show good results during in vitro studies, they fail during in vivo trials. Clinical trials and in vivo testing can aid in better understanding drug targeting and drug uptake mechanisms and overcoming problems such as this. In conclusion, it can be safely said that despite the great advancements exhibited in current research, there still exist several challenges and obstacles to be addressed and overcome.

Acknowledgments This research has been supported by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH
CREATE
INNOVATE (T1EDK-02024)

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Further reading Mao, H.Q., Roy, K., Troung-Le, Vu. L., Janes, K.A., Lin, K.Y., Wang, Y., et al., 2001. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J. Control. Release 70 (3), 399
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